Parkin, a gene with marked allelic heterogeneity including both point mutations and exon rearrangements, accounts for about 50 percent of early onset (< 45 yrs) autosomal recessive cases of Parkinson's disease in Europe. However, the frequency and types of mutations, particularly in late onset cases, their consequences on Parkin expression and the clinical features of the disease are not well known. We will recruit a unique series of PD cases, isolated or familial (autosomal dominant or recessive), with early or late onset, evaluated with standard criteria by a network of movement disorders specialists in Europe, Mediterranean countries, Brazil and Russia, to exhaustively determine the spectrum of parkin mutations and their origin (de novo, founder effects). All patients will be screened by semi quantitative multiplex PCR and DHPLC for mutations in parkin coding sequences. In selected patients with possibly undetected or dominant mutations, coding and promoter regions will be analyzed by combinations of direct sequencing, RT-PCR, Southern blot, FISH to detect mutations affecting regulatory regions or unusual mutational mechanisms (inversions). The consequences of the mutations on mRNA (RT-PCR) and protein (Western blot) expression will pennit correlations between genotypes and phenotypes in relation to their effects on Parkin function and in comparison with other forms of PD. In addition, an association study of 4 polymorphisms in the parkin coding sequence in 400 patients and matched controls will determine whether parkin is a risk factor for other forms of PD. Finally, families excluded from the parkin and the PARK6 loci will be used in a genome-wide search for other loci/genes responsible for early onset autosomal recessive PD. This comprehensive study of the parkin gene will contribute important information both for basic research (consequences of mutations, parkin as a risk factor) and clinical practice (phenotype(s), molecular diagnosis) and enlarge the spectrum of loci/genes responsible for monogenic forms of PD.